A long acting parathyroid hormone PTH(1-34) for treatment of hypoparathyroidism Project Summary Hypoparathyroidism is a rare endocrine disorder characterized by low calcium (Ca2+) and high phosphate (Pi) levels in the setting of absent or low parathyroid hormone (PTH). Overall, an estimated 60,000 to 115,000 individuals in the United States have chronic hypoparathyroidism; most cases (~75%) result from neck surgery, and the remaining are non-surgical or, rarely, genetic disorders. Most hypoparathyroid patients require lifelong high-dose Ca2+ and vitamin D supplements. The associated side effects and the difficulty of maintaining stable serum and urine Ca2+ levels with these regimens makes PTH replacement therapy a desirable or necessary option for many. Two PTH replacement drugs are commonly in use, Natpara, the recombinant form of natural PTH, and teriparatide (Forteo), the 34-amino acid N-terminus polypeptide of the natural hormone. Both these drugs have short half-lives after subcutaneous administration, requiring once-daily injection. Neither adequately mimics the physiological levels of PTH secretion. Indeed, 5 of the 13 members of the FDA Advisory Committee voted against approval of Natpara for hypoparathyroidism, stating that ?dose could be better optimized to closer mimic physiological levels, resulting in more salutary effects?. We have developed a chemically controlled, ultra-long acting delivery system to support once- weekly to once-monthly administration of peptides and other small molecules. With this system a therapeutic agent is covalently attached to a hydrogel microsphere depot by a cleavable ?- eliminative linker. Upon subcutaneous injection the linker slowly cleaves and releases the drug. The current proposal seeks to demonstrate the feasibility of utilizing this system for delivery of PTH. Specifically, we will prepare and characterize two hydrogel microsphere conjugates of PTH(1-34), one suitable for once-weekly and the second suitable for once-monthly administration. Since PTH(1-34) itself is not sufficiently stable for a once-monthly dosing regime, the latter conjugate will be prepared using a more stable PTH(1-34) analog with similar physiological activity. We will perform pharmacokinetic and pharmacodynamic studies of the compounds in thyroid- parathyroidectomized rats to evaluate the potential of one or both these compounds as an improved therapeutic agent for hypoparathyroidism.